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英文药名：SPIRIVA RESPIMAT(tiotropium bromide inhalation spray) 中文药名：噻托嗅按吸入气雾剂 生产厂家：勃林格殷格翰
SPIRIVA RESPIMAT is an anticholinergic indicated for: The long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations (1.1) The long-term, once-daily, maintenance treatment of asthma in patients 12 years of age and older (1.2) Limitation of Use: Not indicated for relief of acute bronchospasm (1.1, 1.2, 5.1) DOSAGE AND ADMINISTRATION For oral inhalation only To receive the full dose of medication, SPIRIVA RESPIMAT must be administered as two inhalations once-daily. Treatment of COPD: 2 inhalations of SPIRIVA RESPIMAT 2.5 mcg once-daily (2) Treatment of asthma patients 12 years and older: 2 inhalations of SPIRIVA RESPIMAT 1.25 mcg once-daily (2) DOSAGE FORMS AND STRENGTHS Inhalation spray: 1.25 mcg or 2.5 mcg tiotropium per actuation with the SPIRIVA RESPIMAT inhaler. Two actuations equal one dose (2.5 mcg or 5 mcg). (3) CONTRAINDICATIONS Hypersensitivity to tiotropium, ipratropium, or any component of this product (4) WARNINGS AND PRECAUTIONS Not for acute use, i.e., not a rescue medication (5.1) Immediate hypersensitivity reactions: Discontinue SPIRIVA RESPIMAT at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, bronchospasm, or anaphylaxis, occur. (5.2) Paradoxical bronchospasm: Discontinue SPIRIVA RESPIMAT and consider other treatments if paradoxical bronchospasm occurs. (5.3) Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.4) Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patient to consult a physician immediately if this occurs. (5.5) ADVERSE REACTIONS The most common adverse reactions in: COPD: (>3% incidence in the placebo-controlled trials with treatment durations of between 4 and 48 weeks) were pharyngitis, cough, dry mouth, and sinusitis. (6.1). Asthma: (>2% incidence in the placebo-controlled trials with treatment durations of between 12 and 52 weeks) were pharyngitis, sinusitis, bronchitis, and headache in adults (6.2). To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SPIRIVA RESPIMAT with other anticholinergic-containing drugs. (7.2) USE IN SPECIFIC POPULATIONS Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects. (2, 8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 1/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease SPIRIVA RESPIMAT (tiotropium bromide) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA RESPIMAT is indicated to reduce exacerbations in COPD patients. Important Limitation of Use: SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Asthma SPIRIVA RESPIMAT is a bronchodilator indicated for the long-term, once-daily, maintenance treatment of asthma in patients 12 years of age and older. Important Limitation of Use: SPIRIVA RESPIMAT is NOT indicated for the relief of acute bronchospasm. 2 DOSAGE AND ADMINISTRATION To receive the full dose of medication, SPIRIVA RESPIMAT must be administered as two inhalations once-daily. Do not take more than one dose (2 inhalations) in 24 hours. Prior to first use, the SPIRIVA RESPIMAT cartridge is inserted into the SPIRIVA RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use [see Patient Counseling Information (17)]. 2.1 Chronic Obstructive Pulmonary Disease The recommended dosage for patients with COPD is 2 inhalations of SPIRIVA RESPIMAT 2.5 mcg per actuation once-daily; total dose equals 5 mcg of SPIRIVA RESPIMAT. 2.2 Asthma The recommended dosage for patients with asthma is 2 inhalations of SPIRIVA RESPIMAT 1.25 mcg per actuation once-daily; total dose equals 2.5 mcg of SPIRIVA RESPIMAT. In the treatment of asthma, the maximum benefits in lung function may take up to 4 to 8 weeks of dosing [see Patient Counseling Information (17)]. 2.3 Special Populations No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given SPIRIVA RESPIMAT should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS SPIRIVA RESPIMAT consists of a SPIRIVA RESPIMAT inhaler and an aluminum cylinder (SPIRIVA RESPIMAT cartridge) containing tiotropium bromide (as the monohydrate). The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler. SPIRIVA RESPIMAT is available in two dosage strengths. Each actuation from the SPIRIVA RESPIMAT inhaler delivers 1.25 mcg or 2.5 mcg of tiotropium (equivalent to 1.562 mcg or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece. Two actuations equal one dose (2.5 mcg or 5 mcg). 4 CONTRAINDICATIONS SPIRIVA RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product [see Warnings and Precautions (5.2)]. In clinical trials with SPIRIVA RESPIMAT, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Not for Acute Use SPIRIVA RESPIMAT is intended as a once-daily maintenance treatment for COPD and asthma and should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. In the event of an acute attack, a rapid-acting beta2-agonist should be used. 5.2 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of SPIRIVA RESPIMAT. If such a reaction occurs, therapy with SPIRIVA RESPIMAT should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to SPIRIVA RESPIMAT. 5.3 Paradoxical Bronchospasm Inhaled medicines, including SPIRIVA RESPIMAT, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with SPIRIVA RESPIMAT should be stopped and other treatments considered. 5.4 Worsening of Narrow-Angle Glaucoma SPIRIVA RESPIMAT should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.5 Worsening of Urinary Retention SPIRIVA RESPIMAT should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.6 Renal Impairment As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA RESPIMAT should be monitored closely for anticholinergic side effects [see Clinical Pharmacology (12.3)]. 6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)] Paradoxical bronchospasm [see Warnings and Precautions (5.3)] Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)] Worsening of urinary retention [see Warnings and Precautions (5.5)] Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice. Since the same active ingredient (tiotropium bromide) is administered to COPD and asthma patients, prescribers and patients should take into account that the observed adverse reactions could be relevant for both patient populations independent of dosage strength. 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The SPIRIVA RESPIMAT clinical development program included ten placebo controlled clinical trials in COPD. Two trials were four-week cross-over trials and eight were parallel group trials. The parallel group trials included a three week dose-ranging trial, two 12-week trials, three 48-week trials, and two trials of 4-week and 24-week duration conducted for a different program that contained tiotropium bromide 5 mcg treatment arms. The primary safety database consists of pooled data from the 7 randomized, parallel-group, double-blind, placebo-controlled studies of 4-48 weeks in treatment duration. These trials included 6565 adult COPD patients (75% males and 25% females) 40 years of age and older. Of these patients, 3282 patients were treated with SPIRIVA RESPIMAT 5 mcg and 3283 received placebo. The SPIRIVA RESPIMAT 5 mcg group was composed mostly of Caucasians (78%) with a mean age of 65 years and a mean baseline percent predicted post-bronchodilator FEV1 of 46%. In these 7 clinical trials, 68.3% of patients exposed to SPIRIVA RESPIMAT 5 mcg reported an adverse event compared to 68.7% of patients in the placebo group. There were 68 deaths in the SPIRIVA RESPIMAT 5 mcg treatment group (2.1%) and 52 deaths (1.6%) in patients who received placebo [see Clinical Studies (14) Long-term active controlled mortality trial: Survival]. The percentage of SPIRIVA RESPIMAT patients who discontinued due to an adverse event were 7.3% compared to 10% with placebo patients. The percentage of SPIRIVA RESPIMAT 5 mcg patients who experienced a serious adverse event were 15.0% compared to 15.1% with placebo patients. In both groups, the adverse event most commonly leading to discontinuation was COPD exacerbation (SPIRIVA RESPIMAT 2.0%, placebo 4.0%) which was also the most frequent serious adverse event. The most commonly reported adverse reactions were pharyngitis, cough, dry mouth, and sinusitis (Table 1). Other adverse reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, dysuria, and urinary retention. Table 1 shows all adverse reactions that occurred with an incidence of >3% in the SPIRIVA RESPIMAT 5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo. Table 1 Number Percentage) of COPD Patients Exposed to SPIRIVA RESPIMAT 5 mcg with Adverse Reactions >3% (and Higher than Placebo): Pooled Data from 7 Clinical Trials with Treatment Periods Ranging between 4 and 48 Weeks in COPD Patients
Other reactions that occurred in the SPIRIVA RESPIMAT 5 mcg group at an incidence of 1% to 3% and at a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo included: Cardiac disorders: palpitations; Gastrointestinal disorders: constipation; gastroesophageal reflux disease; oropharyngeal candidiasis; Nervous system disorders: dizziness; Respiratory system disorders (Upper): dysphonia; Skin and subcutaneous tissue disorders: pruritus, rash; Renal and urinary disorders: urinary tract infection. Less Common Adverse Reactions Among the adverse reactions observed in the clinical trials with an incidence of <1% and at a higher incidence rate on SPIRIVA RESPIMAT 5 mcg than on placebo were: dysphagia, gingivitis, intestinal obstruction including ileus paralytic, joint swelling, dysuria, urinary retention, epistaxis, laryngitis, angioedema, dry skin, skin infection, and skin ulcer. 6.2 Clinical Trials Experience in Asthma Adult Patients SPIRIVA RESPIMAT 2.5 mcg has been compared to placebo in four placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in adult patients (aged 18 to 75 years) with asthma. The safety data described below are based on one 1-year, two 6-month and one 12-week randomized, double-blind, placebo-controlled trials in a total of 2849 asthma patients on background treatment of at least ICS or ICS and long-acting beta agonist (ICS/LABA). Of these patients, 787 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 59.7% were female and 47.5% were Caucasian with a mean age of 43.7 years and a mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1) of 90.0% at baseline. Table 2 shows all adverse reactions that occurred with an incidence of >2% in the SPIRIVA RESPIMAT 2.5 mcg treatment group, and a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo. Table 2 Number (Percentage) of Asthma Patients Exposed to SPIRIVA RESPIMAT 2.5 mcg with Adverse Reactions >2% (and Higher than Placebo): Pooled Data from 4 Adult Clinical Trials with Treatment Periods Ranging between 12 and 52 Weeks in Asthma Patients
Other reactions that occurred in the SPIRIVA RESPIMAT 2.5 mcg group at an incidence of 1% to 2% and at a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo included: Nervous system disorders: dizziness; Gastrointestinal disorders: oropharyngeal, candidiasis, diarrhea; Respiratory system disorders (Upper): cough, rhinitis allergic; Renal and urinary disorders: urinary tract infection; General disorders and administration site conditions: pyrexia; and Vascular disorders: hypertension. Less Common Adverse Reactions Among the adverse reactions observed in the clinical trials with an incidence of 0.5% to <1% and at a higher incidence rate on SPIRIVA RESPIMAT 2.5 mcg than on placebo were: palpitations, dysphonia, acute tonsillitis, tonsillitis, rhinitis, herpes zoster, gastroesophageal reflux disease, oropharyngeal discomfort, abdominal pain upper, insomnia, hypersensitivity (including immediate reactions), angioedema, dehydration, arthralgia, muscle spasms, pain in extremity, chest pain, hepatic function abnormal, liver function test abnormal. Adolescent Patients Aged 12 to 17 years SPIRIVA RESPIMAT 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in adolescent patients with asthma. The safety data described below are based on one 1-year and one 12-week double-blind, placebo-controlled trials in a total of 789 adolescent asthma patients on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 252 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 63.9% were male and 95.6% were Caucasian with a mean age of 14.3 years and a mean post-bronchodilator percent predicted FEV1 of 98.3% at baseline. The adverse reaction profile for adolescent patients with asthma was comparable to that observed in adult patients with asthma. SPIRIVA RESPIMAT 5 mcg also has been compared to placebo in seven placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in 4149 adult patients (aged 18 to 75 years) with asthma and in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in 789 adolescent patients (1370 adults and 264 adolescents receiving SPIRIVA RESPIMAT 5 mcg once-daily). The adverse reaction profile for SPIRIVA RESPIMAT 5 mcg in patients with asthma was comparable to that observed with SPIRIVA RESPIMAT 2.5 mcg in patients with asthma. 6.3 Postmarketing Experience In addition to the adverse reactions observed during the SPIRIVA RESPIMAT clinical trials in COPD, the following adverse reactions have been identified during the worldwide use of SPIRIVA RESPIMAT 5 mcg and another tiotropium formulation, SPIRIVA® HandiHaler® (tiotropium bromide inhalation powder): glaucoma, intraocular pressure increased, vision blurred, atrial fibrillation, tachycardia, supraventricular tachycardia, bronchospasm, glossitis, stomatitis, dehydration, insomnia, hypersensitivity (including immediate reactions), and urticaria. 7 DRUG INTERACTIONS 7.1 Concomitant Respiratory Medications SPIRIVA RESPIMAT has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, and anti-IgE treatment without increases in adverse reactions. 7.2 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SPIRIVA RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. SPIRIVA RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No evidence of structural alterations was observed in rats and rabbits at approximately 790 and 8 times the maximum recommended human daily inhalation dose (MRHDID), respectively (on a mcg/m2 basis at maternal inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, respectively). However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 40 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 430 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m2 basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively). 8.2 Labor and Delivery The safety and effectiveness of SPIRIVA RESPIMAT has not been studied during labor and delivery. 8.3 Nursing Mothers Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if SPIRIVA RESPIMAT is administered to a nursing woman. 8.4 Pediatric Use The safety and efficacy of SPIRIVA RESPIMAT 2.5 mcg have been established in adolescents (aged 12 to 17 years) with asthma in 3 clinical trials up to 1 year in duration [see Clinical Studies (14.2)]. In the 3 clinical trials, 327 patients aged 12 to 17 years with asthma were treated with SPIRIVA RESPIMAT 2.5 mcg. Patients in this age group demonstrated efficacy results similar to those observed in patients aged 18 years and older with asthma. The adverse drug reactions profile for this age group was comparable to that observed for patients aged 18 years and older with asthma. Based on available data, no adjustment of dosage of SPIRIVA RESPIMAT in adolescent patients with asthma is warranted [see Clinical Pharmacology (12.3)]. The safety and efficacy of SPIRIVA RESPIMAT have not been established in pediatric patients less than 12 years of age. 8.5 Geriatric Use Based on available data, no adjustment of SPIRIVA RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)]. Thirty nine percent of SPIRIVA RESPIMAT clinical trial patients with COPD were between 65 and 75 years of age and 14% were greater than or equal to 75 years of age. Approximately seven percent of SPIRIVA RESPIMAT clinical trial patients with asthma were greater than or equal to 65 years of age. The adverse drug reaction profiles were similar in the older population compared to the patient population overall. 8.6 Renal Impairment Patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA RESPIMAT should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. 10 OVERDOSAGE High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium dry powder in 6 healthy volunteers. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects. Treatment of overdosage consists of discontinuation of SPIRIVA RESPIMAT together with institution of appropriate symptomatic and/or supportive therapy. 11 DESCRIPTION The active component of SPIRIVA RESPIMAT is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is:
at week 48 Figure 1 Trough FEV1 Change from Baseline over 48 Weeks (Trial 4), SPIRIVA RESPIMAT 5 mcg
Cause of death was adjudicated by a blinded, independent committee. Cardiovascular deaths included cardiac death, sudden cardiac death, and sudden death; as well as fatal events caused by a cardiac disorder, vascular disorder, or stroke. There were 113 patients (2%) treated with SPIRIVA RESPIMAT 5 mcg who had cardiovascular deaths compared to 101 (2%) patients treated with SPIRIVA HandiHaler. Of the cardiovascular deaths, 11 (0.2%) and 3 (0.1%) deaths were due to myocardial infarction in SPIRIVA RESPIMAT 5 mcg patients and SPIRIVA HandiHaler patients, respectively. For cardiac deaths, sudden cardiac death, and sudden death, there were a total of 69 (1.2%) and 68 (1.2%) deaths in SPIRIVA RESPIMAT 5 mcg patients and SPIRIVA HandiHaler patients, respectively. Effect on Lung Function and Exacerbations In the lung function sub-study the effect of SPIRIVA RESPIMAT 5 mcg on trough FEV1 over 120 weeks was similar to SPIRIVA HandiHaler with a mean difference of -0.010 L (95% CI -0.038 to 0.018 L). Trial 6 also included time to first exacerbation as a co-primary endpoint (exacerbations defined as in Trials 3-5). SPIRIVA RESPIMAT 5 mcg failed to demonstrate superiority to SPIRIVA HandiHaler with a similar time to first COPD exacerbation between treatment groups [hazard ratio of 0.98 (95% CI 0.93 to 1.03)]. 14.2 Asthma The SPIRIVA RESPIMAT clinical development program included five 4-week to 8-week cross-over design trials and seven 12-week to 48-week parallel-arm design trials in adult and adolescent (aged 12 to 17 years) patients with asthma symptomatic on at least ICS. In all trials, SPIRIVA RESPIMAT was administered on a background of ICS therapy. Dose Selection Dose selection for the confirmatory trials was based on three randomized, double-blind, placebo-controlled, 4-week to 8-week, cross-over trials in 256 adult patients and 105 adolescent (age 12 to 17 years) patients that assessed doses ranging from 1.25 mcg to 10 mcg once daily. Results demonstrated numerical improvements in FEV1 at all doses compared to placebo; however, across the trials, the response was not dose-ordered. For adult patients, in the 4-week trial the difference in peak FEV1 within 3 h post-dosing (peak FEV1, 0-3h) from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.138 L (95% CI 0.090, 0.186), 0.128 L (0.080, 0.176), and 0.188 L (0.140, 0.236), respectively. For adolescent patients, the difference in peak FEV1, 0-3h from placebo for the tiotropium RESPIMAT 1.25, 2.5, and 5 mcg doses were 0.067 L (95% CI −0.005, 0.138), 0.057 L (−0.021, 0.135), and 0.113 L (0.036, 0.190), respectively. The 10 mcg dose offered no substantial benefit over lower doses and resulted in more systemic anticholinergic side effects (e.g., dry mouth). The two dose regimen trials in adults with asthma were randomized, double-blind, 4-week, cross-over trials comparing tiotropium RESPIMAT 2.5 mcg twice-daily with 5 mcg once-daily. 24-hour FEV1 results demonstrated comparable treatment effects for twice-daily and once-daily dosing. 12-week to 48-week Parallel-Arm Design Trials in Adults The program for persistent asthma in adult patients included one 12-week (Trial 1), two replicate 24-week (Trials 2 and 3), and two replicate 48-week (Trials 4 and 5) randomized, double-blind, placebo-controlled trials in a total of 3476 asthma patients (673 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 1128 receiving SPIRIVA RESPIMAT 5 mcg once-daily, 541 receiving salmeterol 50 mcg twice daily, and 1134 receiving placebo) on background treatment of at least ICS. Trial 1 evaluated three treatments: SPIRIVA RESPIMAT 2.5 mcg once-daily, SPIRIVA RESPIMAT 5 mcg once-daily, and placebo. Trials 2 and 3 evaluated four treatments: SPIRIVA RESPIMAT 2.5 mcg once-daily, SPIRIVA RESPIMAT 5 mcg once-daily, salmeterol 50 mcg twice daily, and placebo. Trials 4 and 5 evaluated two treatments: SPIRIVA RESPIMAT 5 mcg once-daily and placebo. All trials enrolled patients who had a diagnosis of asthma, were 18 to 75 years of age, and were not current smokers. Patients enrolled in Trials 4 and 5 were required to have airway obstruction that was not fully reversible (post-bronchodilator FEV1/FVC, 0.70). The majority of the 3476 patients in the adult asthma trials were female (60%), Caucasian (61%) or Asian (31%), and had never smoked (81%) with a mean age of 46 years. The patient characteristics for the 12 week to 48 week trials in adult patients with asthma are summarized in Table 5. Table 5 Summary of Baseline Patient Characteristics, Adult Confirmatory Studies
For Trials 1, 2, and 3, SPIRIVA RESPIMAT 2.5 mcg showed statistically significant improvements in lung function over placebo when used in addition to background treatment of ICS (Table 6). Table 6 Differences from Placebo in Peak FEV1, 0-3 and Trough FEV1, Adult Confirmatory Studies at Primary Endpoint Time Evaluation
b Additional asthma medications allowed in stable doses prior to and throughout the trials. c Low dose ICS = 200–400 mcg budesonide-equivalent. Medium dose ICS = 400–800 mcg budesonide-equivalent. Trials 1, 2, and 3 also included a SPIRIVA RESPIMAT 5 mcg once daily treatment arm. In these asthma trials, the FEV1 response (change from baseline for tiotropium compared to placebo) was generally lower for the 5 mcg dose compared to the 2.5 mcg dose. The peak FEV1, 0-3hr response was 16% to 20% lower for the 5 mcg dose compared to the 2.5 mcg dose in all three trials, and, the trough FEV1 response was 11% higher for the 5 mcg dose compared to the 2.5 mcg dose for one trial (Trial 1) and 18% and 24% lower for the 5 mcg dose compared to the 2.5 mcg dose for the other two trials (Trials 2 and 3). Improvements in morning and evening peak expiratory flow (PEF) were consistent with the observed FEV1 treatment response. Examination of age, gender, smoking history, and serum IgE level subgroups did not identify differences in response among these subgroups. The improvement of lung function compared to placebo was maintained for 24 hours (Figure 2). The bronchodilator effects of SPIRIVA RESPIMAT 2.5 mcg were apparent after first dose; however, maximum bronchodilator effect took up to 4 to 8 weeks to be achieved. Figure 2 FEV1 Response over 24-Hours following 24-Weeks of Treatment, Trial 3
ACQ and AQLQ were assessed in Trials 2 and 3 at week 24. In Trial 2, the ACQ-7 (7 items) responder rate (defined as a change in score >0.5) for the SPIRIVA RESPIMAT 2.5 mcg treatment arm was 63% compared to 53% for placebo with an odds ratio of 1.47 (95% CI 1.02, 2.11). The ACQ-5 (derived from ACQ 7 by removing the FEV1 component and rescue bronchodilator component) results also had a similar trend. In Trial 2, the AQLQ responder rate (defined as a change in score >0.5) for the SPIRIVA RESPIMAT 2.5 mcg treatment arm was 58% compared to 50% for placebo with an odds ratio of 1.34 (95% CI 0.94, 1.93). 12-week and 48-week Parallel-Arm Design Trials in Adolescents 12-17 Years of Age Efficacy in adolescents was based on partial extrapolation of efficacy in adults and two randomized, double-blind, placebo-controlled trials of 12 and 48 weeks duration in a total of 789 asthma patients 12 to 17 years of age (252 receiving SPIRIVA RESPIMAT 2.5 mcg once-daily, 264 receiving 5 mcg once-daily, and 273 receiving placebo). Both trials included SPIRIVA RESPIMAT 2.5 mcg and 5 mcg doses. The 12-week trial enrolled patients with severe asthma who were on background treatment of ICS plus one or more controller medications (e.g. LABA). The 48-week trial enrolled patients with moderate asthma on background treatment of at least ICS. The majority of the patients in the trials were male (63.4%), Caucasian (93.7%) and had never smoked (99.9%) with a mean age of 14.3 years. The primary efficacy endpoint in both trials was change from pre-treatment baseline in peak FEV1, 0-3h. The primary endpoint evaluation for FEV1 was defined at week 24 for the 48-week trial and at end of the treatment period (week 12) for the 12-week trial. Given the demonstration of efficacy in the adult population, the results of the 2 trials support the efficacy of SPIRIVA RESPIMAT 2.5 mcg once daily in adolescent patients 12-17 years of age with asthma (mean difference in peak FEV1, 0-3h from placebo for SPIRIVA RESPIMAT 2.5 mcg were 0.13 L (95% CI 0.03, 0.23) and 0.11 (0.002, 0.22) for the 48-week and 12-week trials, respectively). 16 HOW SUPPLIED/STORAGE AND HANDLING SPIRIVA RESPIMAT Inhalation Spray is supplied in a carton containing one SPIRIVA RESPIMAT cartridge and one SPIRIVA RESPIMAT inhaler. The SPIRIVA RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The SPIRIVA RESPIMAT cartridge is only intended for use with the SPIRIVA RESPIMAT inhaler and should not be interchanged with any other RESPIMAT device delivered product. The SPIRIVA RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The written information on the label of the gray inhaler body indicate that it is labeled for use with the SPIRIVA RESPIMAT cartridge. SPIRIVA RESPIMAT Inhalation Spray is available in two dosage strengths, identified by dose delivered per actuation and by the color of the cap and associated container label: aqua represents 2.5 mcg per actuation; blue represents 1.25 mcg per actuation. To deliver the recommended dosage for COPD: SPIRIVA RESPIMAT Inhalation Spray 2.5 mcg/actuation 60 metered actuations(NDC 0597-0100-61) SPIRIVA RESPIMAT Inhalation Spray 2.5 mcg/actuation 28 metered actuations(NDC 0597-0100-31) (institutional pack) To deliver the recommended dosage for asthma: SPIRIVA RESPIMAT Inhalation Spray 1.25 mcg/actuation 60 metered actuations(NDC 0597-0160-61) SPIRIVA RESPIMAT Inhalation Spray 1.25 mcg/actuation 28 metered actuations(NDC 0597-0160-31) (institutional pack) The SPIRIVA RESPIMAT cartridge for each strength has a net fill weight of 4 grams and when used with the SPIRIVA RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations (60 or 28) after preparation for use; which is, respectively, equivalent to 30 or 14 days of medication when used according to the Instructions for Use. Each actuation from the SPIRIVA RESPIMAT inhaler delivers 1.25 or 2.5 mcg of tiotropium (equivalent to 1.562 or 3.124 mcg, respectively, of tiotropium bromide monohydrate) from the mouthpiece. When the labeled number of actuations (60 or 28) has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed. After assembly, the SPIRIVA RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first. Keep out of reach of children. Do not spray into eyes. Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid freezing. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b656b14-fcaa-2741-f6f0-e0be48971c02
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SPIRIVA RESPIMAT(tiotropium bromide inhalation spray)简介：
英文药名：SPIRIVA RESPIMAT(tiotropium bromide inhalation spray)
中文药名：噻托嗅按吸入气雾剂
生产厂家：勃林格殷格翰药品介绍Spiriva Respimat第一类新的吸入气雾剂获FDA批准2014年9月26日，美 ... 责任编辑：admin |
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